EP2170058A1 - Inhibiteurs de cetp dérivés de benzoxazole arylamides - Google Patents

Inhibiteurs de cetp dérivés de benzoxazole arylamides

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Publication number
EP2170058A1
EP2170058A1 EP08768488A EP08768488A EP2170058A1 EP 2170058 A1 EP2170058 A1 EP 2170058A1 EP 08768488 A EP08768488 A EP 08768488A EP 08768488 A EP08768488 A EP 08768488A EP 2170058 A1 EP2170058 A1 EP 2170058A1
Authority
EP
European Patent Office
Prior art keywords
group
optionally substituted
phenyl
optionally
ocf3
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP08768488A
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German (de)
English (en)
Other versions
EP2170058B1 (fr
EP2170058A4 (fr
Inventor
Julianne A. Hunt
Ramzi F. Sweis
Dooseop Kim
Florida Kallashi
Peter J. Sinclair
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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Publication of EP2170058A1 publication Critical patent/EP2170058A1/fr
Publication of EP2170058A4 publication Critical patent/EP2170058A4/fr
Application granted granted Critical
Publication of EP2170058B1 publication Critical patent/EP2170058B1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to a class of chemical compounds that inhibit cholesterol ester transfer protein (CETP) and therefore have utility in raising HDL-cholesterol, lowering LDL-cholesterol, and in the treatment and prevention of atherosclerosis.
  • CETP cholesterol ester transfer protein
  • CHD coronary heart disease
  • stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
  • CHD coronary heart disease
  • stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
  • CHD coronary heart disease
  • stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
  • CHD coronary heart disease
  • stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
  • CHD coronary heart disease
  • HMG-CoA Reductase inhibitors especially the statins
  • LDL-C Low Density Lipoprotein cholesterol
  • epidemiologic studies have demonstrated an inverse relationship between High Density Lipoprotein cholesterol (HDL-C) levels and atherosclerosis, leading to the conclusion that low serum HDL-C levels are associated with an increased risk for CHD.
  • cholesteryl ester transfer protein a plasma glycoprotein that catalyzes the movement of cholesteryl esters from HDL to the apoB containing lipoproteins, especially VLDL (see Hesler, CB. , et. al. (1987) Purification and characterization of human plasma cholesteryl ester transfer protein. J. Biol. Chem. 262(5), 2275-2282)).
  • CETP cholesteryl ester transfer protein
  • VLDL cholesteryl ester transfer protein
  • CETP plays a role in reverse cholesterol transport, the process whereby cholesterol is returned to the liver from peripheral tissues.
  • many animals do not possess CETP, including animals that have high HDL levels and are known to be resistant to coronary heart disease, such as rodents (see Guyard-Dangremont, V., et. al., (1998)
  • statins represent, statins only achieve a risk reduction of approximately one-third in the treatment and prevention of atherosclerosis and ensuing atherosclerotic disease events.
  • few pharmacologic therapies are available that favorably raise circulating levels of HDL-C.
  • Certain statins and some fibrates offer modest HDL-C gains.
  • Niacin which provides the most effective therapy for raising HDL-C that has been clinically documented, suffers from patient compliance issues, due in part to side effects such as flushing.
  • An agent that safely and effectively raises HDL cholesterol levels can answer a significant, but as yet unmet medical need by offering a means of pharmacologic therapy that can significantly improve circulating lipid profiles through a mechanism that is complementary to existing therapies.
  • Compounds having Formula I are CETP inhibitors, and have utility in raising HDL-cholesterol, lowering LDL- cholesterol, and in treating, preventing, and/or reducing the risk of developing atherosclerosis:
  • Q is selected from the group consisting of O, S, and -N(R2)-;
  • A is a difunctional cyclic group selected from 1 ,4-phenylene, 2,5-pyridinylene, and 2,5-pyrimidinylene, wherein A is optionally substituted with 1-3 substituent groups Rl;
  • Each Rl is independently selected from the group consisting of halogen, Ci-C3alkyl, C2-C3alkenyl, C2-C3alkynyl, and -OCi-C3alkyl, wherein each alkyl, alkenyl, and alkynyl substituent is optionally substituted with 1-5 halogens;
  • Each R2 is independently selected from the group consisting of H, Ci-C3alkyl, C2-C3 alkenyl, and C2-C3 alkynyl, wherein each alkyl, alkenyl, and alkynyl substituent is optionally substituted with 1-5 halogens;
  • RY is selected from the group consisting of halogen, CH3, CF3, -OCH3, -OCF3, -CN, phenyl, and a 6-membered heteroaroaromatic group having 1-2 N, wherein phenyl and the 6-membered heteroaroaromatic group are optionally substituted with 1 -3 substituents independently selected from halogen, CH3, CF3, -OCH3, and -OCF3;
  • RX and RZ are each selected from the group consisting of H, halogen, CH3, CF3, -OCH3, and -OCF3;
  • B is selected from the group consisting of:
  • R3 is selected from the group consisting of H and Ci-C3alkyl
  • R5 is selected from the group consisting of H, Ci-C3alkyl, and CF3;
  • R7 is selected from the group consisting of H, Ci-C3alkyl, CF3 5 and phenyl, which is optionally substituted with 1-3 groups independently selected from halogen, CH3, CF3, -OCH3, and -OCF3; x is 0 or 1 ; y is O, 1, or 2; p is 0 or 1 ; q is 0, 1, or 2, with the proviso that p and q are not both 0;
  • D2 is a cyclic group selected from (a) 4-membered and 6-8 membered saturated and partly unsaturated heterocyclic groups, and (b) a spirocyclic group having two rings joined by a spirocyclic linkage through a carbon atom wherein each ring is a 5-7-membered ring, wherein D2 comprises one ring member -N(R8)-, optionally 1-2 ring members independently selected from -O- and -S-, optionally one carbonyl group, and optionally 1 -2 double bonds, wherein D2 or a ring of D2 is optionally fused to a phenyl ring or to a C5-C7Cycloalkyl, wherein
  • D2 is connected to the remainder of the structure represented by Formula I through a carbon atom of D2, wherein D2 is optionally substituted with 1-3 substituents independently selected from halogen, -CN, -NO2, -N(R3)2-, Ci-C3alkyl, CF3, -OCH3, phenyl, pyridyl, and -OCF3, and optionally with 1 group Ci-C5alkylene-phenyl, wherin phenyl and pyridyl in all uses are optionally substituted with 1-3 substituent groups independently selected from halogen, CH3, CF3, -OCH3, and -OCF3; D3 is a heterocyclic group selected from (a) a saturated or partly unsaturated 4-8 membered monocyclic heterocyclic group, (b) a saturated or partly unsaturated bicyclic heterocyclic group wherein each ring is a 5-8-membered ring, and (c) a spirocyclic group having two rings joined by a
  • Ci-C9alkyl and Ci-C6alkyl groups in all uses are optionally substituted with 1-9 halogens;
  • Each R.9 is independently selected from the group consisting of H, Ci-C7alkyl,
  • Ci-C7alkyl, C2-C7alkenyl, and C2-C7alkynyl are optionally substituted with 1 -9 halogens.
  • alkyl, alkenyl and alkynyl groups can be linear or branched, unless otherwise stated.
  • Q is O.
  • A is a difunctional cyclic group selected from 1 ,4-phenylene, 2,5-pyridinylene, and 2,5-pyrimidinylene, wherein A is optionally substituted with 1-3 substiruent groups Rl.
  • each Rl is independently selected from the group consisting of halogen, CH3, CF3, -OCH3, and -OCF3.
  • RY is selected from the group consisting of halogen, CH3, CF3, -OCH3, -OCF3, and -CN.
  • RX and RZ are each selected from the group consisting of H, halogen, CH3, CF3, -OCH3, and -OCF3.
  • R3 is selected from the group consisting of H and CH3.
  • R6 is H
  • R7 is selected from the group consisting of H and phenyl, which is optionally substituted with 1-3 groups independently selected from halogen, CH3, CF3, -OCH3, and -OCF3.
  • D2 is selected from the group consisting of azetidine, piperidine, morpholine, a saturated 7-membered heterocyclic ring which comprises one -O- and one -N- in the ring, and a spirocyclic group comprising a cyclopentane ring and a piperidine ring joined by a spirocyclic linkage through a commonly shared carbon atom, wherein D2 is connected to the right hand side of the structure of Formula Ia through a carbon atom of D2, wherein said carbon atom of D2 that is connected to the right hand side of Formula Ia is optionally substituted with one group selected from phenyl, pyridyl, and Ci- C3alkyl optionally substituted with 1-3F, wherein the phenyl and pyridyl groups are optionally substituted with one group selected from CH3, CF3,
  • D3 is selected from the group consisting of (a) a 5-7-membered saturated cyclic amine; (b) a 6-7 membered saturated cyclic diamine; (c) a 5-6 membered saturated cyclic amine connected by a spirocyclic linkage through a shared carbon atom to a 5-6 membered cyclic ether, a 5-6 membered cycloalkyl, or a second 5-6 membered saturated cyclic amine, wherein one N atom of D3 is connected to the right hand side of the structure of Formula Ia, and the second N atom of D3, if present, is connected to the group R.8, wherein D3 is optionally substituted with one substitutent group selected from CH3, CF3, -OCH3, -OCF3, halogen, phenyl, and -(CH2)l-3phenyl, wherein phenyl and the phenyl group of (CH2) 1-3 phenyl are
  • D4 is selected from the group consisting of pyrimidinyl, pyridyl, phenyl, C3-C6cycloalkyl, naphthyl, and quinolyl, and is optionally substituted with 1-3 groups independently selected from halogen, Ci-C4alkyl, C2-C5alkenyl, CF3, -OCi-G ⁇ dkyl, -OCF3, -CO2H, -CO2Ci-C3alkyl, -N(CH3)2, -NO2, -CN, and optionally one cyclic group D6 which is bonded directly to D4 or is bonded to a difunctional linking group ⁇ which is bonded to D4-
  • D6 is selected from the group consisting of piperidinyl, phenyl, cyclopropyl, cyclohexyl, cyclohexenyl, and pyrazolyl, and is optionally substituted with 1-3 substituents independently selected from Ci-C4alkyl optionally substituted with 1-3F, -0Ci-C4alkyl optionally substituted with 1-3F, halogen, and optionally one phenoxy; and ⁇ is optionally C2-C3alkenylene.
  • Alk alkoxy and alkanoyl
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
  • Alkylene groups are alkyl groups that are difunctional rather than monofunctional. For example, methyl is an alkyl group and methylene (-CH2-) is the corresponding alkylene group.
  • alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2- butenyl, and the like.
  • Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.
  • Cycloalkyl means a saturated carbocyclic ring having from 3 to 8 carbon atoms, unless otherwise stated (e.g., cycloalkyl may be defined as having one or more double bonds). The term also includes a cycloalkyl ring fused to an aryl group.
  • cycloalkyl examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Cycloalkenyl means a non- aromatic carbocyclic ring having one or more double binds.
  • Aryl (and “arylene") when used to describe a substituent or group in a structure means a monocyclic or bicyclic compound in which the rings are aromatic and which contains only carbon ring atoms.
  • aryl can also refer to an aryl group that is fused to a cycloalkyl or heterocycle.
  • Preferred "aryls” are phenyl and naphthyl. Phenyl is generally the most preferred aryl group.
  • EDC is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
  • Heterocyclyl means a fully or partially saturated or aromatic 5-6 membered ring containing 1-4 heteroatoms independently selected from N, S and O, unless otherwise stated.
  • “Benzoheterocycle” represents a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms, each of which is O, N, or S, where the heterocyclic ring may be saturated or unsaturated. Examples include indole, benzofuran, 2,3- dihydrobenzofuran and quinoline.
  • DIPEA diisopropylethylamine
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • HBT 1-Hydroxybenzotriazole
  • IPAC is isopropyl acetate.
  • Me represents methyl.
  • Weight amine is N,O-dimethylhydroxylamine.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the substituent "tetrazole” means a 2//-tetrazol-5-yl substituent group and tautomers thereof.
  • Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • the present invention is meant to include all such stereoisomeric forms of the compounds of Formula I and all mixtures of the compounds.
  • all stereochemical structures are included individually and collectively, such as enantiomers, diastereomers (where diastereomers are possible), and mixtures of the enantiomers and/or diastereomers, including racemic mixtures.
  • any reference to stereoisomers of the compound includes other enantioners, diasteroeomers (when possible), and mixtures of these, including racemic mixtures.
  • Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. Some of the compounds described herein may exist as tautomers. An example is a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I.
  • Compounds of Formula I having one or more asymmetric centers may be separated into diastereoisomers, enantiomers, and the like by methods well known in the art.
  • enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and/or reagents of known configuration.
  • biphenyl and biaryl compounds herein are observed as mixtures of atropisomers (rotamers) in the NMR spectra.
  • the individual atropisomers as well as mixtures thereof are encompassed with the compounds of this invention.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • Therapeutically active metabolites where the metabolites themselves fall within the scope of the claimed invention, are also compounds of the current invention.
  • Prodrugs which are compounds that are converted to the claimed compounds as they are being administered to a patient or after they have been administered to a patient, are also compounds of this invention.
  • Compounds of the current invention are potent inhibitors of CETP. They are therefore useful in treating diseases and conditions that are treated by inhibitors of CETP.
  • One aspect of the present invention provides a method for treating or reducing the risk of developing a disease or condition that may be treated or prevented by inhibition of CETP by administering a therapeutically effective amount of a compound of this invention to a patient in need of treatment.
  • a patient is a human or mammal, and is most often a human.
  • a "therapeutically effective amount” is the amount of compound that is effective in obtaining a desired clinical outcome in the treatment of a specific disease.
  • Diseases or conditions that may be treated with compounds of this invention, or which the patient may have a reduced risk of developing as a result of being treated with the compounds of this invention include: atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity, endotoxemia, and metabolic syndrome.
  • the compounds of this invention are particularly effective in raising HDL-C and/or increasing the ratio of HDL-C to LDL-C.
  • the compounds are also effective in lowering LDL-C. These changes in HDL-C and LDL-C may be beneficial in treating atherosclerosis, reducing or reversing the development of atherosclerosis, reducing the risk of developing atherosclerosis, or preventing atherosclerosis.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of Formula I are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds of the present invention are administered at a daily dosage of from about 0.01 milligram to about 100 milligram per kilogram of animal or human body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form, hi the case of a 70 kg adult human, the total daily dose will generally be from about 0.5 milligram to about 500 milligrams.
  • the dosage for an adult human may be as low as 0.1 mg.
  • the dosage regimen may be adjusted within this range or even outside of this range to provide the optimal therapeutic response.
  • Oral administration will usually be carried out using tablets.
  • Examples of doses in tablets are 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, and 500 mg.
  • Other oral forms can also have the same dosages (e.g. capsules).
  • compositions which comprise a compound of Formula I and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt as an active ingredient, as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • a pharmaceutical composition may also comprise a prodrug, or a pharmaceutically acceptable salt thereof, if a prodrug is administered.
  • Pharmaceutical compositions may also consist essentially of a compound of Formula I and a pharmaceutically acceptable carrier without other thereapeutic ingredients.
  • compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous), hi preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • compositions and preparations should contain at least 0.1 percent of active compound.
  • the percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Compounds of the invention may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases or conditions for which compounds of Formula I are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred.
  • the combination therapy also includes therapies in which the compound of Formula I and one or more other drugs are administered on different schedules.
  • the drugs When oral formulations are used, the drugs may be combined into a single combination tablet or other oral dosage form, or the drugs may be packaged together as separate tablets or other oral dosage forms. It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
  • HMG-CoA reductase inhibitors which are generally statins, including lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, pravastatin, and other statins
  • bile acid sequestrants cholesterolestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran, Colestid®, LoCholest®
  • niacin and related compounds such as nicotinyl alcohol, nicotinamide, and nicotinic acid or a salt thereof,
  • PP ARa agonists which are generally statins, including lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, pravastatin, and other statins
  • Preferred classes of therapeutic compounds that can be used with the compounds of this invention for use in improving a patient's lipid profile include one or both of statins and cholesterol absorption inhibitors.
  • Particularly preferred are combinations of compounds of this invention with simvastatin, ezetimibe, or both simvastatin and ezetimibe.
  • Also preferred are combinations of compounds of this invention with statins other than simvastatin, such as lovastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, and ZD-4522.
  • compounds of this invention can be used with compounds that are useful for treating other diseases, such as diabetes, hypertension and obesity, as well as other anti- atherosclerostic compounds.
  • Such combinations may be used to treat one or more of such diseases as diabetes, obesity, atherosclerosis, and dyslipidemia, or more than one of the diseases associated with metabolic syndrome.
  • the combinations may exhibit synergistic activity in treating these disease, allowing for the possibility of administering reduced doses of active ingredients, such as doses that otherwise might be sub-therapeutic.
  • active ingredients that may be administered in combination with a compound of this invention include, but are not limited to, compounds that are primarily anti-diabetic compounds, including:
  • PPAR gamma agonists and partial agonists including glitazones and non- glitazones (e.g. pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512, and LY-818;
  • glitazones and non- glitazones e.g. pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512, and LY-818;
  • PTP-IB protein tyrosine phosphatase- IB
  • dipeptidyl peptidase IV (DP-IV) inhibitors including vildagliptin, sitagliptin, and saxagliptin
  • insulin or insulin mimetics such as for example insulin lispro, insulin glargine, insulin zinc suspension, and inhaled insulin formulations
  • sulfonylureas such as tolbutamide, glipizide, glimepiride, acetohexamide, chlorpropamide, glibenclamide, and related materials;
  • ⁇ -glucosidase inhibitors such as acarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q; and salbostatin
  • PPAR ⁇ / ⁇ dual agonists such as muraglitazar, tesaglitazar, farglitazar, and naveglitazar
  • PPAR ⁇ agonists such as GW501516 and those disclosed in WO97/28149;
  • glucagon receptor antagonists such as GW501516 and those disclosed in WO97/28149;
  • GLP-I GLP-I
  • GLP-I derivatives GLP-I analogs, such as exendins, such as for example exenatide (Byetta); and non-peptidyl GLP-I receptor agonists
  • GIP-I GLP-I receptor agonists
  • Non-sulfonylurea insulin secretagogues such as the meglitinides (e.g.nateglinide and rapeglinide).
  • antiobesity compounds including 5-HT(serotonin) inhibitors, neuropeptide Y5 (NP Y5) inhibitors, melanocortin 4 receptor (Mc4r) agonists, cannabinoid receptor 1 (CB-I) antagonists/inverse agonists, and ⁇ 3 adrenergic receptor agonists. These are listed in more detail later in this section.
  • active ingredients also include active ingredients that are used to treat inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors, including etoricoxib, celecoxib, rofecoxib, and Bextra.
  • active ingredients that are used to treat inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors, including etoricoxib, celecoxib, rofecoxib, and Bextra.
  • COX-2 selective cyclooxygenase-2
  • Antihypertensive compounds may also be used advantageously in combination therapy with the compounds of this invention.
  • antihypertensive compounds include (1) angiotensin II antagonists, such as losartan; (2)angiotensin converting enzyme inhibitors (ACE inhibitors), such as enalapril and captopril; (3) calcium channel blockers such as nifedipine and diltiazam; and (4) endothelian antagonists.
  • Anti-obesity compounds may be administered in combination with the compounds of this invention, including: (1) growth hormone secretagogues and growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, and MK-0677; (2) protein tyrosine phosphatase- IB (PTP-IB) inhibitors; (3) cannabinoid receptor ligands, such as cannabinoid CBi receptor antagonists or inverse agonists, such as rimonabant (Sanofi) growth hormone secretagogues and growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, and MK-0677; (2) protein tyrosine phosphatase- IB (PTP-IB) inhibitors; (3) cannabinoid receptor ligands, such as cannabinoid CBi receptor antagonists or inverse agonists, such as rimonabant (Sanofi
  • Opioid antagonists such as nalmefene (Revex ®), 3-methoxynaltrexone, naloxone, and naltrexone; (49) glucose transporter inhibitors; (50) phosphate transporter inhibitors; (51) 5 -HT (serotonin) inhibitors; (52) beta-blockers; (53) Neurokinin-1 receptor antagonists (NK-I antagonists); (54) clobenzorex; (55) cloforex; (56) clominorex; (57) clortermine; (58) cyclexedrine; (59) dextroamphetamine; (60) diphemethoxidine, (61) N-ethylamphetamine; (62) fenbutrazate; (63) fenisorex; (64) fenproporex; (65) fludorex; (66) fluminorex; (67) furfurylmethylamp
  • Opioid antagonists such as nalmefene (Revex
  • a patient having metabolic syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high-density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic.
  • Each of these symptoms is defined clinically in the recently released Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No.
  • Patients with metabolic syndrome have an increased risk of developing the macro vascular and microvascular complications that are listed above, including atherosclerosis and coronary heart disease.
  • the combinations described above may ameliorate more than one symptom of metabolic syndrome concurrently (e.g. two symptoms, three symptoms, four symptoms, or all five of the symptoms).
  • Synthetic cholesteryl ester (CE) donor HDL particles contained DOPC (Dioleoyl Phosphatidyl Choline), BODIPY®-CE (Molecular Probes C-3927), triolein (a triglyceride), dabcyl dicetylamide, (a non-diffusable quencher molecule to reduce background fluorescence) and apoHDL.
  • Synthetic triglyceride (TG) donor HDL particles contained DOPC, BODIPY®-TG, and apoHDL.
  • BODIPY ®-TG was synthesized at room temperature from diolein and the BODIPY containing fatty acid analog 4,4-difluoro-5-(2- thienyl)-4-bora-3a,4a-diaza-s-indacene-3-dodecanoic acid (Molecular Probes) in methylene chloride in the presence of dicyclohexyl carbodimide. Dabcyl dicetylamide was made by heating dabcyl n-succinimide with dicetylamine in DMF at 95 °C overnight in the presence of diisopropylamine catalyst. Native lipoproteins from human blood were used as acceptor particles.
  • Particles having a density less than 1.063 g/ml were collected by ultracentrifugation. These particles include VLDL, IDL, and LDL. Particle concentrations were expressed in terms of protein concentration as determined by BCA assay (Pierce, USA). Particles were stored at 4°C until use.
  • Assays were performed in Dynex Microfluor 2 U-bottom black 96-well plates (Cat #7205).
  • An assay cocktail containing CETP, IX CETP buffer (50 rnM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA), 3% human serum, and half the final concentration of acceptor particles was prepared, and 100 ⁇ L of the assay cocktail was added to each well of the plate.
  • Test compounds in DMSO were added in a volume of 3 ⁇ L. The plate was mixed on a plate shaker and then incubated at 25 °C for 1 hour. A second assay cocktail containing donor particles, the remaining acceptor particles and IX CETP buffer was prepared.
  • fluorescence plate reader Molecular Devices Spectramax GeminiXS
  • TG transfer reactions were performed as described above with the exception that 2.5 ng/uL TG donor particles were used. TG transfer was measured at an excitation wavelength of 538 nm while reading emission at 568 nm every 45 sec for 45 min at 37°C with a cutoff filter at 550 nm. Data were evaluated by obtaining an initial rate, expressed in relative fluorescence units per second, for the pseudolinear portion of the curve, often 0-500 or 1000 sec. Comparison of the rates of samples with inhibitors to an uninhibited (DMSO only) positive control yielded a percent inhibition. A plot of percent inhibition vs. log of inhibitor concentration, fit to a Sigmoidal 4 parameter equation was used to calculate IC50.
  • IC50 values are in the range of 13 nM to 21 uM. Most of the compounds have an IC50 value of 13 nM — 200 nM, and the preferred compounds generally have IC50 values of 13 nM - 100 nM. Each of the following representative compounds, or a stereoisomer thereof, has an IC50 value in the range of 13nM to 6OnM: Examples 1, 3, 19-23, 27-33, and 58.
  • Step B Methyl 4-(5-cvano-7-isopropyl-l,3-benzoxazol-2-yl)benzoate
  • Step C 4-(5-Cvano-7-isopropyl-l,3-benzoxazol-2-yl)benzoic acid
  • Step A tert-ButvK ⁇ 1 -
  • Step B l- ⁇ l-r4-(Trifluoromethyl)phenyllpiperidin-4-yl) methanamine
  • a mixture of trifluoroacetic acid (10 ml) and dichloromethane (10 ml) was added to tert- butyl( ⁇ l-[4-(trifluoromethyl)phenyl]piperidin-4-yl ⁇ methyl)carbamate (1.36 g). This mixture was stirred at room temperature for 3 h. The sample was concentrated and taken up in dichloromethane (20 ml) and saturated aqueous sodium bicarbonate. The mixture was extracted and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (1.21 g, 86%).
  • Step A Lithium 4-(5-cvano-7-isopropyl-l,3-benzoxazol-2-yl ' )benzoate
  • Step. A 4-(5-Cvano-7-isopropyl-l,3-benzoxazol-2-yl)-N- ⁇ ri-( ' 2-isopropenylpyrimidin-4- yl)piperidin-4-yl "
  • Step B 4-(5-Cyano-7-isopropyl- 1 ,3-benzoxazol-2-yl)-N- ⁇ F 1 -(2-isopropylpyrimidin-4- vDpiperidin-4-ylimethyl ⁇ benzamide
  • Step A 4-Nitrobenzyl 4-( ⁇ r4-(5-cvano-7-isopropyl-l,3-benzoxazol-2- vDbenzoyli amino ⁇ methvDpiperidine- 1 -carboxvlate
  • Step B 3,5-Bis(trifluoromethyl)benzyl 4-( ⁇ [4-(5-cyano-7-isopropyl-l,3-benzoxazol-2- vDbenzoyli amino ⁇ methyl)piperidine- 1 -carboxylate
  • the reaction mixture was purified by flash chromatography on a Biotage Horizon, 25 S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes.
  • the resulting mixture was repurified by reverse-phase HPLC: Kromasil C18 21 x 100 mm column, eluting at 15 ml/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (7.9 mg, 0.015 mmol, 19.79 % yield).
  • Step A Benzyl ⁇ 3-[4-( ⁇ r4-(5-cyano-7-isopropyl-l.,3-benzoxazol-2-yl)benzoyl1ainino ⁇ methvDpiperidin- 1 -yl] -3 -oxopropyl ⁇ carbamate
  • Step B N-rd-IN-rS.S-BisftrifluoromethvDcvclohexyli- ⁇ -alanvUpiperidin ⁇ -v ⁇ methyli ⁇ -rS- cyano-7-isopropyl- 1 ,3 -benzoxazol-2-yl)benzamide
  • Step A fert-Butyl 4-(aminocarbonvO-4-isopropylpiperidine-l-carboxylate
  • oxalyl chloride 2.76 ml, 5.53 mmol
  • dimethylformamide 2.76 ml, 5.53 mmol
  • Step B tert-Butyl 4-cvano-4-isopropylpiperidine-l-carboxylate
  • Step C tert-Butyl 4-( ⁇ [4-(5-cvano-7-isopropyl-l,3-benzoxazol-2-yl)benzovHamino ⁇ methyl)-4- isopropylpiperidine- 1 -carboxylate
  • the aqueous phase was extracted with 2 x 20 ml of ethyl acetate, and then the combined organics were washed with brine, dried(sodium sulfate), and concentrated.
  • the residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 column volume of
  • tert-butyl (piperidin-3 -ylmethyl)carbamate (643 mg), followed by l-(bromomethyl)-4- (trifluoromethyl)benzene (717 mg).
  • the mixture was heated to 7O 0 C and stirred for 0.5 h.
  • the sample was filtered through a small plug of silica gel and concentrated in vacuo to provide tert- butyl( ⁇ l-[4-(trifluoromethyl)benzyl]piperidin-3-yl ⁇ methyl)carbamate (640 mg).
  • Step A 4-(5-Cyano-7-isopropyl-l ,3-benzoxazol-2-ylViV-r(35 ⁇ -piperidin-3-ylmethyllbenzamide
  • Step B 4-r5-Cvano-7-isopropyl-13-benzoxazol-2-yl)-N-( ⁇ ( ' 3J?Vl-r3- ⁇ rifluoromethvnbenzyll piperidin-3 - yl ⁇ methvDbenzamide
  • Step A Benzyl (75 f )-7-( ⁇ [4-( ' 5-cvano-7-isopropyl-l,3-benzoxazol-2-yl)benzoyllamino ⁇ methyl- 1 ,4-oxazepane-4-carboxylate
  • Step B 4-(5-Cyano-7-isopropyl- 1 ,3-benzoxazol-2-yl)-N-[(7S)- 1 ,4-oxazepan-7-ylmethyl] benzamide
  • Step A ⁇ -fMethoxycarbonvDnicotinic acid
  • Step B Methyl-5-([Y ⁇ l-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-vUmethyl)amino1 car bonyl ⁇ pyridine-2-carboxylate To a solution of 6-(methoxycarbonyl)nicotinic acid (250 mg, 1.39 mmol) and l- ⁇ l-[4-
  • Step C 5- ⁇ [( ⁇ 1 -[4-(Trifluoromethyl)pyrimidin-2-yl]piperidin-4-vUmethyl)amino1 carbonvUpyridine-2-carboxylic acid
  • a suspension of methyl-5- ⁇ [( ⁇ l-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4- yl ⁇ methyl)amino] carbonyl ⁇ pyridine-2-carboxylate (272 mg, 0.643mmol) in tetrahydrofuran, methanol, and water (5 ml, in a ratio of 3:2:1, respectively) was added lithium hydroxide (108 mg, 2.57 mmol).
  • Step D N-(5-Cvano-2-hvdroxy-3-isopropylphenylVN-( ⁇ l-[4-(trifluoromethyl)pyrimidin-2- yllpiperidin-4-yl ⁇ methyl)pyridine-2 , 5 -dicarboxamide
  • Step E 6-(5-Cvano-7-isopropyl-l,3-benzoxazol-2-ylV N -( ⁇ l-r4-(trifluoromethyl)pyrimidin-2- vl]piperidin-4-yl ⁇ methvDni cotinamide
  • Step B Methyl-2-vinylpyrimidine-5-carboxvlate To a solution of methyl-2-chloropyrimidine-5-carboxylate (2.084 g, 12.08 mmol) and tributyl(vinyl)tin (3.635 g, 11.46 mmol) in toluene (15 ml) was added triphenylphosphine (94.9 mg, 0.362 mmol) followed by tetrakis(triphenylphosphine) palladium(O) (418.5 mg, 0.362 mmol). The mixture was stirred at 11O 0 C for 10 h under anhydrous argon.
  • Step D Methyl-2-(5-cvano-7-isopropyl- 1 ,3-benzoxazol-2yl)pyrirnidine-5-carboxylate
  • Methyl-2-formylpyrimidine-5-carboxylate 200 mg, 1.205 mmol
  • 3-amino-4-hydroxy-5- isopropylbenzonitrile 212 mg, 1.205 mmol
  • dichloromethane 5 ml
  • 2,3-dichloro-5,6-dicyano-p-benzoquinone 300.9 mg, 1.325 mmol
  • the solution was stirred at room temperature for 30 min, and then concentrated.
  • the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution.
  • Step E 2-(5-Cyano-7-isopropyl-1.3-benzoxazol-2yl)pyrimidine-5-carboxylic acid
  • Step F 2-(5-Cvano-7-isopropyl-l .3-benzoxazol-2yl)-iV-( ⁇ l-[4-(trifluoromethyr)pyrimidine-2- ylipiperidi-4-yl ⁇ methyl)pyrimidine-5 -carboxamide
  • 2-(5-cyano-7-isopropyl-l,3-benzoxazol-2yl)pyrimidine-5-carboxylic acid (30 mg, 0.097 mmol)
  • l- ⁇ l-[4-(trifluoromethyl)pyrimidine-2-yl]piperidi-4-yl ⁇ methanamine (INTERMEDIATE 6, 25.3 mg, 0.097 mmol) in dimethylformamide (2 ml) were added hydroxybenzotriazole (15.7 mg, 0.116 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.9 mg, 0.
  • the mixture was cooled to room temperature, diluted with water (300 ml) and acetic acid (-50 ml), and then extracted with ethyl acetate (5 x 300 ml).
  • the organic layers were dark red-brown to light green-yellow in succession.
  • the combined organic layers were extracted with water (2 x 300 ml) and then 2M sodium hydroxide (3 x 300 ml).
  • the aqueous layers were red to yellow in succession.
  • the combined aqueous layers (containing the phenol) were made slightly acidic by addition of 100 ml of acetic acid and then extracted with ethyl acetate (3 x 300 ml). These organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step A 4 tgrt-Butyl4-( ⁇ r4-(5-cvano-7-methyl-1.3-benzoxazol-2-yl)benzoyl1amino ⁇ methvDpiperidine- 1 -carboxylate
  • the title compound was synthesized from methyl 4-(5-cyano-7-methyl-l,3-benzoxazol-2- yl)benzoate (INTERMEDIATE 22) following the procedure described in EXAMPLE 105.
  • Step B 4-(5-Cvano-7-methyl-13-benzoxazol-2-ylVN-( ⁇ l-[4-( ' trifluoromethyl) benzyl] piperidin- 4-yl ⁇ methvDbenzamide
  • Step B 4-(5-Cvano-7-isopropenyl-1.3-benzoxazol-2-yl ' )-N-( ⁇ l-[5-( ' trifluoromethyl ' ) pyridin-2- yl]piperidin-4-yl > methvDbenzamide
  • Step B 4- ⁇ [Y( l-[4-(Trifluoromethyl)pyrimidin-2-yl1piperidin-4-vUmethyl)aminol carbonvU benzoic acid
  • Methyl 4- ⁇ [( ⁇ 1 - [4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4- yl ⁇ methyl)amino]carbonyl ⁇ benzoate was dissolved in 24 ml of tetrahydrofuran, 23 ml of methanol, and 23 ml of water. To this solution was added lithium hydroxide (817 mg) and the mixture was stirred at 5O 0 C for 1.25 h. The solvents were removed in vacuo and the residue was taken up in 1 N HCl (70 ml) and 70 ml of ethyl acetate. The mixture was sonicated until the solid residue mostly dissolved in the ethyl acetate.
  • Step B Ethyl 5-cyano-2-(4- ⁇ [( ' ⁇ l-[4-(trifluoromethyl)pyrimidin-2-yllpiperidin-4-yl ⁇ methv ⁇ amino1carbonyl ⁇ phenylM,3-benzoxazole-7-carboxylate
  • Step A 4-(7-Bromo-5-cvano-l,3-benzoxazol-2-yl)-N-( ⁇ l-[4-(trifluoromethyl)pyrimidin-2- yllpiperidin-4-yl ⁇ methvDbenzamide
  • Step B 4- ( 5-Cvano-7- [ (IZ)-I -methylprop- 1 -en- 1 -yll - 1.3 -benzoxazol-2-yl ) -N-( ⁇ 1 - [4- (trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl ⁇ methyl)benzamide
  • Step C 4-(7-sec-Butyl-5-cyano-l,3-benzoxazol-2-vD-./V-( ⁇ l-[4-(trifluoromethyl)pyrimidin-2- yl]piperidin-4-yl ⁇ methvDbenzamide
  • Step A 4- ⁇ IY4-Carboxybenzoyl)aminolmethyl I - 1 -r5-(trifluorornethvOpyridin-2-yl]piperidiniurn chloride
  • Step B 4-(7-Bromo-5-cyano-1.3-benzoxazol-2-yl)-iV-( ⁇ l-r5-( ' trifluoromethv ⁇ pyridin-2- yl]piperidin-4-yl ⁇ methvDbenzamide
  • Step D 4-(7-sec-Butyl-5-cvano-h3-benzoxazol-2-yl)-iV-( ⁇ l-[5-(trifluoromethyl)pyridin-2- yll piperidiri-4-yl ⁇ methvDbenzamide
  • Step E 4-[5-Cyano-7-(methylthio)-l,3-benzoxazol-2-yl "
  • benzoic acid The title compound was prepared from methyl 4-[5-cyano-7-(methylthio)-l,3-benzoxazol-2- yljbenzoate by a procedure analogous to that described in INTERMEDIATE 2, Step C. Mass spectrum (ESI) 311.0 (M+ 1).
  • Step F 4-r5-Cvano-7-(methylthioV1.3-benzoxazol-2-yl1-N-((l-r5-(trifluoromethyl)pyridin-2- yllpiperidin-4-yl ⁇ methyPbenzamide
  • Step B 2-(4-Bromophenyl)-7-( 1 -hydroxy- 1 -methylethyl)- 1 ,3 -benzoxazole-5-carbonitrile
  • Step C 2-(4-Bromophenyl)-7- ⁇ -fluoro-l-methylethyl)-l,3-benzoxazole-5-carbonitrile
  • Step D Methyl 4-r5-cvano-7-(l-fluoro-l-methylethv ⁇ -l,3-benzoxazol-2-yllbenzoate
  • Step E 4-r5-Cvano-7-(l-fluoro-l-methylethvn-l,3-benzoxazol-2-yl1-iV-( ⁇ l-r5- (trifluoromethyl)pyridin-2-yl]piperidin-4-yl ⁇ methyPbenzamide
  • Step A 4-Hvdroxy-3-(trifluoromethoxy * )benzoic acid
  • Step B 2-[4-(2,8-Diazaspiro[4.51dec-2-ylcarbonyl)phenyl]-7-isopropyl-l,3-benzoxazole-5- carbonitrile
  • Step C 7-Isopropyl-2-r4-( ' (8-r4-( ' trifluoromethyl)pyrimidin-2-yl1-2,8-diazaspiror4.51dec-2- yl ⁇ carbonvDphenyl]- 1 ,3-benzoxazole-5-carbonitrile
  • 2-[4-(2,8-diazaspiro[4.5]dec-2-ylcarbonyl)phenyl]-7-isopropyl-l,3- benzoxazole-5-carbonitrile 25 mg, 0.046 mmol
  • potassium carbonate 13 mg, 0.094 mmol
  • 2-chloro-4-(trifluoromethyl)pyrimidine 10 ⁇ l, 0.083 mmol.
  • the reaction mixture was heated to 50°C and stirred at this temperature overnight, at which point LC/MS analysis showed a peak at the desired molecular weight.
  • the reaction mixture was purified by flash chromatography on a Biotage Horizon, 25 S column, eluting with 1 column volume of
  • Step A tert-Butyl-4-( 1 - ⁇ F4-(5 -cyano-7-isopropyl- 1 ,3 -benzoxazol-2-yPbenzoyli amino ⁇ -2- methoxy-2-oxoethyl)piperidine- 1 -carboxylate.
  • Step B Methyl ⁇ r4-(5-cvano-7-isopropyl-l,3-benzoxazol-2-yl)benzoyl1aminoKpiperidin-4- vPacetate

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Abstract

L'invention concerne des composés présentant une structure de formule I, ainsi que des sels acceptables sur le plan pharmaceutique desdits composés, qui sont de puissants inhibiteurs de CETP (protéine de transfert des esters de cholestérol), qui sont utiles pour augmenter le HDL cholestérol, réduire le LDL cholestérol, et qui permettent de traiter ou de prévenir l'athérosclérose. L'athérosclérose et ses conséquences cliniques, les coronaropathies (CHD), les AVC et maladies vasculaires périphériques, représentent un véritable fardeau pour les systèmes de soins de santé dans le monde industrialisé. Dans la formule I, A-B est un fragment arylamide.
EP08768488.2A 2007-06-20 2008-06-16 Inhibiteurs de cetp dérivés de benzoxazole arylamides Not-in-force EP2170058B1 (fr)

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US8436028B2 (en) 2007-06-20 2013-05-07 Merck Sharp & Dohme Corp CETP inhibitors derived from benzoxazole arylamides
US8293721B2 (en) 2007-06-20 2012-10-23 Merck Sharpe & Dohme Corp. CETP inhibitors derived from benzoxazole arylamides
MX2013000359A (es) * 2010-07-09 2013-02-11 Ube Industries Compuesto de piridina sustituida.
ES2650744T3 (es) * 2010-12-14 2018-01-22 Electrophoretics Limited Inhibidores de la caseína quinasa 1 delta (CK1delta)
AU2012311698B2 (en) * 2011-09-22 2017-06-22 Merck Sharp & Dohme B.V. N-piperidin-4-yl derivatives
CA2860601C (fr) 2012-01-06 2016-07-05 Daiichi Sankyo Company, Limited Sel d'addition d'acide de compose de pyridine substitue
WO2014099836A1 (fr) 2012-12-19 2014-06-26 Merck Sharp & Dohme Corp. Inhibiteurs de la cetp spirocycliques
WO2014099834A1 (fr) 2012-12-20 2014-06-26 Merck Sharp & Dohme Corp. Composés de thiazolidinone thérapeutiques
EP3027619B1 (fr) 2013-07-30 2019-01-02 Merck Sharp & Dohme Corp. Urées bicycliques et thiadiazolidine-1,1-dioxydes servant d'inhibiteurs de cetp
EP3054945B1 (fr) 2013-10-10 2018-08-15 Merck Sharp & Dohme Corp. Indolines 3,3'-disubstituées utilisées comme inhibiteurs de la protéine de transfert du cholestérol estérifié
CN106414432B (zh) 2013-10-14 2019-06-14 卫材R&D管理有限公司 选择性取代的喹啉化合物
RU2671496C2 (ru) 2013-10-14 2018-11-01 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Производные 5-пиперидин-8-цианохинолина
US9594070B2 (en) * 2013-11-05 2017-03-14 Spectrum Tracer Services, Llc Method using halogenated benzoic acid esters and aldehydes for hydraulic fracturing and for tracing petroleum production
LT3081566T (lt) * 2013-12-13 2018-05-25 Daiichi Sankyo Company, Limited 5-hidroksi-4-(trifluormetil)pirazolpiridino darinys
US9663534B2 (en) 2013-12-17 2017-05-30 Merck Sharp & Dohme Corp. Fused bicyclic isoxazolines as inhibitors of cholesterol ester transfer protein
WO2016018729A1 (fr) 2014-07-29 2016-02-04 Merck Sharp & Dohme Corp. Isoxazolines monocycliques utilisées comme inhibiteurs de la protéine de transfert des esters de cholestérol
WO2016021706A1 (fr) * 2014-08-08 2016-02-11 カズマパートナーズ株式会社 Composé hétérocyclique condensé
EP3350158A4 (fr) 2015-09-16 2019-05-08 Metacrine, Inc. Agonistes du récepteur x farnésoïde et leurs utilisations
DK3350165T3 (da) 2015-09-16 2023-09-25 Organovo Inc Farnesoid-X-receptoragonister og anvendelser deraf
WO2017049177A1 (fr) 2015-09-16 2017-03-23 Metacrine, Inc. Agonistes du récepteur x farnésoïde et leurs utilisations
JP2018536016A (ja) * 2015-09-16 2018-12-06 メタクリン，インク． ファルネソイドｘ受容体アゴニストとその使用
CN105541777A (zh) * 2016-01-29 2016-05-04 中国药科大学 异黄酮酰胺类衍生物、其制备方法和医药用途
US10017684B2 (en) * 2016-04-20 2018-07-10 Spectrum Tracer Services, Llc Method and compositions for hydraulic fracturing and for tracing formation water
GB202000011D0 (en) * 2020-01-02 2020-02-19 Syngenta Crop Protection Ag Improvements in or relating to organic compounds

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995030659A1 (fr) * 1994-05-10 1995-11-16 Warner-Lambert Company Derives de benzimidazoles et d'imidazopyridines, leur preparation et leur utilisation comme agents dopaminergiques hautement selectifs vis-a-vis des recepteurs d3 de la dopamine
WO2001000587A1 (fr) * 1999-06-24 2001-01-04 Smithkline Beecham P.L.C. Azolylbenzamide et analogues et leur utilisation pour traiter l'osteoporose
WO2004019869A2 (fr) * 2002-08-29 2004-03-11 Merck & Co., Inc. Indoles presentant un effet antidiabetique
WO2007070173A2 (fr) * 2005-10-31 2007-06-21 Merck & Co., Inc. Inhibiteurs de la cetp

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS615071A (ja) * 1984-06-15 1986-01-10 Fuji Photo Film Co Ltd ベンゾオキサゾ−ル誘導体
US4714762A (en) * 1986-10-31 1987-12-22 Warner-Lambert Company Antiarteriosclerotic substituted benzimidazol-2-yl-and 3H-imidazo[4,5-b]pyridin-2-yl-phenoxy-alkanoic acids and salts and esters thereof
EP0503838A3 (en) * 1991-03-08 1992-10-07 Merck & Co. Inc. Heterocyclic compounds bearing acidic functional groups as angiotensin ii antagonists
CA2062558A1 (fr) * 1991-03-08 1992-09-09 Prasun K. Chakravarty Composes heterocycliques portant des groupes fonctionnels acides, utilises comme antagonistes de l'angiotensine ii
GB9317949D0 (en) * 1993-08-28 1993-10-13 Stevens Malcolm F G Benzothiazole compounds
US5874431A (en) * 1993-08-28 1999-02-23 Cancer Research Campaign Technology Limited Benzazole compounds
ATE248153T1 (de) 1994-10-12 2003-09-15 Euro Celtique Sa Neue benzoxazole
US5885983A (en) * 1996-05-10 1999-03-23 Bristol-Myers Squibb Company Inhibitors of microsomal triglyceride transfer protein and method
AR008789A1 (es) * 1996-07-31 2000-02-23 Bayer Corp Piridinas y bifenilos substituidos
CA2315070A1 (fr) * 1997-12-17 1999-07-01 Schering Aktiengesellschaft Derives d'(ortho)-anthranilamide comme anticoagulants
AR022462A1 (es) 1999-02-06 2002-09-04 Astrazeneca Uk Ltd Uso de un agente que disminuye el colesterol
AU5636900A (en) * 1999-06-30 2001-01-31 Merck & Co., Inc. Src kinase inhibitor compounds
GB9919673D0 (en) 1999-08-20 1999-10-20 Cancer Res Campaign Tech 2-Arlybenzazole compounds
US6861533B2 (en) * 2001-11-23 2005-03-01 Irm Llc Solution phase sythesis of arylbenzoxazoles
DOP2005000123A (es) * 2004-07-02 2011-07-15 Merck Sharp & Dohme Inhibidores de cetp
US8293721B2 (en) 2007-06-20 2012-10-23 Merck Sharpe & Dohme Corp. CETP inhibitors derived from benzoxazole arylamides
US8436028B2 (en) 2007-06-20 2013-05-07 Merck Sharp & Dohme Corp CETP inhibitors derived from benzoxazole arylamides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995030659A1 (fr) * 1994-05-10 1995-11-16 Warner-Lambert Company Derives de benzimidazoles et d'imidazopyridines, leur preparation et leur utilisation comme agents dopaminergiques hautement selectifs vis-a-vis des recepteurs d3 de la dopamine
WO2001000587A1 (fr) * 1999-06-24 2001-01-04 Smithkline Beecham P.L.C. Azolylbenzamide et analogues et leur utilisation pour traiter l'osteoporose
WO2004019869A2 (fr) * 2002-08-29 2004-03-11 Merck & Co., Inc. Indoles presentant un effet antidiabetique
WO2007070173A2 (fr) * 2005-10-31 2007-06-21 Merck & Co., Inc. Inhibiteurs de la cetp

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2008156715A1 *

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WO2008156715A1 (fr) 2008-12-24
CA2689575A1 (fr) 2008-12-24
US8445480B2 (en) 2013-05-21
EP2170058B1 (fr) 2013-07-03
JP2010530416A (ja) 2010-09-09
US20100298288A1 (en) 2010-11-25
EP2170058A4 (fr) 2010-07-28
AU2008266954A1 (en) 2008-12-24

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